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ContextLittle is known about the frequency of key mutations in thyroid cancer metastases and its relationship with the primary tumor genotype.ObjectivesTo evaluate the frequency of TERT promoter (TERTp), BRAF, and NRAS mutations in metastatic thyroid carcinomas, analyzing primary thyroid tumors, lymph node metastases (LNMs), and distant metastases.Design and PatientsMutation analysis was performed in 437 tissue samples from 204 patients, mainly with papillary thyroid carcinomas (PTCs; n = 180), including 196 LNMs and 56 distant metastases. All the distant metastases included corresponded to radioiodine-refractory metastatic tissue.ResultsWe found the following mutation frequency in primary PTCs, LNMs, and distant metastases, respectively: TERTp: 12.9%, 10.5%, and 52.4%; BRAF: 44.6%, 41.7%, and 23.8%; and NRAS: 1.2%, 1.3%, and 14.3%. There was a significant concordance between the primary tumor genotype and the corresponding LNM for all the genes, in particular BRAF-mutated PTC. The overall concordance between primary tumors and respective distant metastases was low. In the group of patients with PTCs, we found a high frequency of TERTp mutations and a low frequency of BRAF mutations in distant metastases, in comparison with the paired primary tumors. When present in distant metastases, BRAF mutations frequently coexisted with TERTp mutations.ConclusionsWhen the genotype of primary tumors is compared with the genotype of LNMs, the concordance is high for all the genes studied. On the other hand, distant metastases show an enrichment in TERTp mutations and a decrease in BRAF mutations. TERTp mutations may play a role in distant metastases.We evaluated the frequency of TERT, BRAF, and NRAS mutations in thyroid tumors, lymph node, and distant metastases. Distant metastases show an enrichment in TERTp and a decrease in BRAF mutations.

Background Tumor-to-tumor metastasis is a rare event. Rectal cancer to primary thyroid neoplasm metastasis is extremely rare. Herein, we reported a case of metastatic rectal adenocarcinoma to a papillary thyroid carcinoma. The incidence and clinicopathological characteristics of metastatic colorectal cancer to a thyroid gland neoplasm were described, and the pertinent literature was reviewed. Case presentation A 34-year-old female patient had curative treatment of initial rectal adenocarcinoma in 2012, and was found to have lung metastases by follow-up CT scan 3 years later. In 2018, she was found to have thyroid metastasis by imaging due to left neck pain and hoarseness. A fine-needle aspiration biopsy (FNAB) result suggested suspicious papillary thyroid carcinoma (PTC). The patient underwent a total thyroidectomy and bilateral cervical lymph nodes dissection. The histopathology of thyroidectomy specimen revealed a rectal adenocarcinoma metastatic to the thyroid concomitant with the papillary carcinoma in metastatic adenocarcinoma. The patient received levothyroxine supplementation therapy and palliative chemotherapy with irinotecan and anti-angiogenesis for the metastatic rectal adenocarcinoma. After 1 year of thyroidectomy, no newly developed lesion evidence of recurrent PTC was observed. The patient remains still alive. Conclusion The possibility of metastases should be considered in patients with a history of rectal cancer and with a thyroid lesion, particularly in those with ageing, hereditary nonpolyposis colorectal cancer (HNPCC) or long-term survival. The diagnosis should be histologically confirmed for the presence of both primary thyroid lesions and secondary thyroid neoplasms. Thyroidectomy may be a feasible treatment for symptomatic thyroid metastasis or thyroid cancer. we need to gain more available evidence from large or multi-center clinical data to help clinicians to diagnose rectal cancer to thyroid neoplasm metastases and evaluate treatment.

No effective standard treatment exists for patients with radioiodine-refractory, advanced differentiated thyroid carcinoma. We aimed to assess efficacy and safety of vandetanib, a tyrosine kinase inhibitor of RET, VEGFR and EGFR signalling, in this setting. In this randomised, double-blind, phase 2 trial, we enrolled adults (aged ≥18 years) with locally advanced or metastatic differentiated thyroid carcinoma (papillary, follicular, or poorly differentiated) at 16 European medical centres. Eligible patients were sequentially randomised in a 1:1 ratio with a standard computerised scheme to receive either vandetanib 300 mg per day (vandetanib group) or matched placebo (placebo group), balanced by centre. The primary endpoint was progression-free survival (PFS) in the intention-to-treat population based on investigator assessment. This study is registered with ClinicalTrials.gov, number NCT00537095. Between Sept 28, 2007, and Oct 16, 2008, we randomly allocated 72 patients to the vandetanib group and 73 patients to the placebo group. By data cutoff (Dec 2, 2009), 113 (78%) patients had progressed (52 [72%] patients in the vandetanib group and 61 [84%] in the placebo group) and 40 (28%) had died (19 [26%] patients in the vandetanib group and 21 [29%] in the placebo group). Patients who received vandetanib had longer PFS than did those who received placebo (hazard ratio [HR] 0·63, 60% CI 0·54–0·74; one-sided p=0·008): median PFS was 11·1 months (95% CI 7·7–14·0) for patients in the vandetanib group and 5·9 months (4·0–8·9) for patients in the placebo group. The most common grade 3 or worse adverse events were QTc prolongation (ten [14%] of 73 patients in the vandetanib group vs none in the placebo group), diarrhoea (seven [10%] vs none), asthenia (five [7%] vs three [4%]), and fatigue (four [5%] vs none). Two patients in the vandetanib group and one in the placebo group died from treatment-related serious adverse events (haemorrhage from skin metastases and pneumonia in the vandetanib group and pneumonia in the placebo group). Vandetanib is the first targeted drug to show evidence of efficacy in a randomised phase 2 trial in patients with locally advanced or metastatic differentiated thyroid carcinoma. Further investigation of tyrosine-kinase inhibitors in this setting is warranted. AstraZeneca.

Background Metastasis to the thyroid gland from nonthyroid sites is an uncommon clinical presentation in surgical practice. The aim of this review was to assess its incidence management and outcomes. Methods A literature review was performed to identify reports of metastases to the thyroid gland. Both clinical and autopsy series were included. Results Metastases to the gland may be discovered at the time of diagnosis of the primary tumor, after preoperative investigation of a neck mass, or on histologic examination of a thyroidectomy specimen. The most common primary tumors in autopsy studies are from the lung. In clinical series, renal cell carcinoma is most common. For patients with widespread metastases in the setting of an aggressive malignancy, surgery is rarely indicated. However, when patients present with an isolated metastasis diagnosed during follow-up of indolent disease, surgery may achieve control of the central neck and even long-term cure. Other prognosticators include features of the primary tumor, time interval between initial diagnosis and metastasis, and extrathyroid extent of disease. Conclusions In patients with thyroid metastases, communication among clinicians treating the thyroid and the index primary tumor is essential. The setting is complex, and decisions must be made considering the features of the primary tumor, overall burden of metastases, and comorbidities. Careful balancing of these factors influences individualized approaches.

Chemotherapy has historically proven ineffective in advanced differentiated thyroid cancers, but the realisation that various tyrosine kinases are activated in the disease suggested a potential therapeutic role for tyrosine-kinase inhibitors. We investigated the safety and efficacy of pazopanib. This phase 2 trial was done from Feb 22, 2008, to Jan 31, 2009, in patients with metastatic, rapidly progressive, radioiodine-refractory differentiated thyroid cancers. Each patient received 800 mg continuous pazopanib daily in 4-week cycles until disease progression, drug intolerance, or both occurred. Up to two previous therapies were allowed, and measurable disease with radiographic progression in the 6-month period before enrolment was a requirement for inclusion. The primary endpoint was any tumour response, according to the Response Evaluation Criteria in Solid Tumors 1.0. This study is registered with ClinicalTrials.gov, number NCT00625846. 39 patients were enrolled. One patient had received no previous radioiodine therapy and another withdrew consent before treatment. Clinical outcomes could, therefore, be assessed in 37 patients (19 [51%] men, median age 63 years). The study is closed to accrual of new patients, but several enrolled patients are still being treated. Patients received a median of 12 cycles (range 1 to >23, total >383). Confirmed partial responses were recorded in 18 patients (response rate 49%, 95% CI 35–68), with likelihood of response lasting longer than 1 year calculated to be 66%. Maximum concentration of pazopanib in plasma during cycle one was significantly correlated with radiographic response ( r=−0·40, p=0·021). 16 (43%) patients required dose reductions owing to adverse events, the most frequent of which (any grade) were fatigue (29 patients), skin and hair hypopigmentation (28), diarrhoea (27), and nausea (27). Two patients who died during treatment had pre-existing contributory disorders. Pazopanib seems to represent a promising therapeutic option for patients with advanced differentiated thyroid cancers. The correlation of the patient's response and pazopanib concentration during the first cycle might indicate that treatment can be individualised to achieve optimum outcomes. Assessment of pazopanib in an expanded cohort of patients with differentiated thyroid cancer, as well as in cohorts of patients with medullary and anaplastic thyroid cancers, is presently being done. National Cancer Institute, supported in part by NCI CA15083 and CM62205.

Abstract Context A subset of thyroid carcinomas expresses an oncogenic paired box 8 (PAX8) and peroxisome proliferator activated receptor γ (PPARγ) fusion protein (PPFP). The PPARγ/PPFP ligand pioglitazone is highly therapeutic in a transgenic mouse model of PPFP thyroid carcinoma, but whether pioglitazone is therapeutic in patients with PPFP thyroid carcinoma is unknown. Case Description Tumor blocks from 40 patients with progressive thyroid cancer despite standard-of-care therapy were screened for PPFP, and the tumor from only one patient (2.5%) was positive. The patient had a 6.0-cm acetabular soft tissue metastasis from Hürthle cell carcinoma that caused severe pain on weight bearing and had a serum thyroglobulin level of 1974 ng/mL. After 24 weeks of therapy with pioglitazone, the metastatic lesion was 3.9 cm, the thyroglobulin level was 49.4 ng/mL, and the patient was pain-free. Thirteen months after discontinuation of pioglitazone, the metastatic lesion was 3.6 cm, the thyroglobulin level was 4.7 ng/mL, and the patient remained pain-free. Conclusions Pioglitazone may be therapeutic in patients with PPFP thyroid cancer. However, thyroid cancers that are progressive despite standard-of-care therapy appear to only rarely express PPFP. A patient with PPFP-positive thyroid cancer had a major clinical improvement, as well as radiological and biochemical improvements, after therapy with pioglitazone was begun.

Long noncoding RNAs (lncRNAs) are emerging as important regulators in the development of cancer cells. However, the role and mechanisms of most lncRNAs in papillary thyroid carcinoma (PTC) remain unknown. In this study, we investigated lncRNA expression profiles of PTC using RNA-seq in two groups of PTC tissues and adjacent normal tissues, and validated by real-time PCR analysis in another 53 pairs of tissues. We identified a novel lncRNA, n384546, which is highly expressed in PTC tissues and cell lines. n384546 expression was associated with clinicopathological features of PTC patients, such as tumor size, lymph node metastasis, and TNM stage. Functionally, knockdown of n384546 inhibited PTC cell proliferation, invasion, and migration both in vitro and in vivo. In addition, we identified miR-145-5p as a key miRNA target of n384546 using online bioinformatics tools. Anti-miR-145 could partially reverse the effects of n384546 knockdown. Furthermore, we found that n384546 could regulate the expression of AKT3 by sponging miR-145-5p, which was confirmed using an in vitro luciferase assay. In conclusion, we validated n384546 as a novel oncogenic lncRNA in PTC and determined that the n384546/miR-145-5p/AKT3 pathway contributes to PTC progression, which might be used as potential therapeutic targets for PTC patients.

Background The tall cell variant of papillary thyroid carcinoma (PTC) is as an aggressive histological variant. The proportion of tall cells needed to influence prognosis is debated. Methods Patients with PTC and tall cells, defined as having a height-to-width ratio of ≥ 3:1, seen at a high-volume center between 2001 and 2015, were reviewed. Specimens were classified as (1) focal tall cell change, containing < 30% of tall cells; (2) tall cell variant, ≥ 30% of tall cells; and (3) control cases selected from infiltrative classical PTCs without adverse cytologic features. Univariate, sensitivity, and multivariate analyses were performed with persistent/recurrent disease as the primary outcome. Results We identified 96 PTCs with focal tall cell change, 35 with the tall cell variant and 104 control cases. Factors associated with poor clinical prognosis were significantly greater in those with focal tall cell change and tall cell variants. Regarding primary outcome, hazard ratios were 2.3 (95% confidence interval [CI] 1.0–5.7) for focal tall cell change, and 3.4 (95% CI 1.2–8.7) for tall cell variants compared with controls. Five-year disease-free survival was higher for the control group (92.7%, CI 87.4–98.0) compared with focal tall cell change (76.3%, CI 66.1–86.5) and the tall cell variant (62.2%, CI 43.2–81.2). When stratified in groups consisting of tall cell proportions (< 10%, 10–19%, 20–29% and ≥ 30%), identification of ≥ 10% tall cell change was associated with worse outcome ( p  = 0.002). Conclusions PTCs with ≥ 10% tall cell change have worse prognosis than those without tall cells. Our data indicate that thyroid cancer management guidelines should consider PTCs with focal tall cell change outside of the low-risk classification.

Abstract Context Metastatic medullary thyroid cancer (MTC) is a rare malignancy with minimal treatment options. Many, but not all, MTCs express somatostatin receptors. Objective Our aim was to explore the role of 68Ga-DOTA-somatostatin analogue (SSA) positron emission tomography (PET)/computed tomography (CT) in patients with metastatic MTC and to determine their eligibility for peptide receptor radionuclide therapy (PRRT). Methods We retrospectively identified patients with metastatic MTC who had 68Ga-DOTA-SSA PET/CT at 5 centers. We collected characteristics on contrast-enhanced CT, 68Ga-DOTA-SSA and 18F-FDG PET/CT. The efficacy of PRRT was explored in a subgroup of patients. Kaplan-Meier analysis was used to estimate time to treatment failure (TTF) and overall survival (OS). Results Seventy-one patients were included (10 local recurrence, 61 distant disease). Of the patients with distant disease, 16 (26%) had ≥50% of disease sites with tracer avidity greater than background liver, including 10 (10/61, 16%) with >90%. In 19 patients with contemporaneous contrast-enhanced CT, no disease regions were independently identified on 68Ga-DOTA-SSA PET/CT. Thirty-five patients had an 18F-FDG PET/CT, with 18F-FDG positive/68Ga-DOTA-SSA negative metastases identified in 15 (43%). Twenty-one patients had PRRT with a median TTF of 14 months (95% CI 8-25) and a median OS of 63 months (95% CI 21-not reached). Of the entire cohort, the median OS was 323 months (95% CI 152-not reached). Predictors of poorer OS included a short calcitonin doubling-time (≤24 months), strong 18F-FDG avidity, and age ≥60 years. Conclusions The prevalence of high tumor avidity on 68Ga-DOTA-SSA PET/CT is low in the setting of metastatic MTC; nevertheless, PRRT may still be a viable treatment option in select patients.

Background Delphian lymph node (DLN) metastasis is a recognized indicator of further lymph node involvement in papillary thyroid carcinoma (PTC). The aim of this study was to evaluate the clinicopathological significance of and risk factors for DLN metastasis. Methods The medical records of 1,436 patients who underwent primary thyroidectomy for classical PTC with a tumor size of 2 cm or less were reviewed. Of these, 370 patients from whom the DLN was harvested were enrolled. Metastasis in DLN was present in 46 patients and absent in 324 patients. Clinicopathological features were compared according to DLN metastasis. Results In univariate analysis, DLN metastasis was associated with suspected lymph node metastasis on preoperative ultrasonography, tumor location in the isthmus or upper third of the thyroid, larger tumor size, extrathyroid extension, lymphovascular invasion, and further lymph node metastasis. Multivariable analysis revealed that DLN metastasis was associated with tumor location in the isthmus or upper third of the thyroid (odds ratio [OR] = 2.420; 95 % confidence interval [CI] 1.193–4.910) and further lymph node metastasis (OR = 4.746; 95 % CI 2.065–10.908). Conclusions DLN metastasis in PTC is associated with tumor location in the isthmus or upper third of the thyroid and unfavorable clinicopathological characteristics. Careful consideration and patient management are warranted when preoperative ultrasonography indicates that the tumor is located in the isthmus or upper third of the thyroid.